JPH0892233A - Method for producing n-formyl-l-aspartic acid anhydride purpose - Google Patents

Abstract

PURPOSE: To effectively obtain N-formyl-L-aspartic acid anhydride crystal reduced in the content of remaining formic acid, when the anhydride is produced and the produced suspension is separated. CONSTITUTION: In the method for producing N-formyl-L-aspartic acid anhydride by reacting L-aspartic acid with acetic anhydride and formic acid in an amount of >=10 times moles to that of the aspartic acid, the following operations (1), (2) and (3) are performed when the produced N-formyl-L-aspartic acid anhydride suspension is centrifuged in the presence or absence of an aromatic hydrocarbon. (1) The supply of the suspension into the separator is started in the state wherein a back pressure of >=100[mmHg] is applied, (2) the back pressure is eliminated when at least a half of the suspension is supplied, and (3) the filtration and/or the removal of the liquid from the wet cake are subsequently performed, and if necessary, the cake is further washed.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a dipeptide sweetener α
The present invention relates to a method for producing N-formyl-L-aspartic anhydride, which is an intermediate for the production of L-aspartyl-L-phenylalanine methyl ester. Furthermore, N synthesized using N-formyl-L-aspartic acid anhydride as a raw material
-Formyl-α-L-aspartyl-L-phenylalanine and N-formyl-α-L-aspartyl-L
-A method for producing phenylalanine methyl ester.

[0002]

N-formyl-L-aspartic acid anhydride (hereinafter referred to as "anhydride") is usually obtained by reacting L-aspartic acid with formic acid and acetic anhydride (hereinafter, this reaction is referred to as "anhydride reaction"). ). At that time, there is known a method of using an approximately stoichiometric amount of acetic anhydride and formic acid with respect to aspartic acid (JP-A-59-4627).
9, JP-A-63-63699), there is a problem that the yield of the anhydride is low with respect to aspartic acid which is the starting material.

In order to increase the yield of this dehydration reaction,
It is necessary to use an excess amount of formic acid and acetic anhydride with respect to aspartic acid, but in that case, a large amount of unreacted formic acid remains at the end of the reaction. Α as the final product
If L-aspartyl-L-phenylalanine methyl ester (hereinafter referred to as α-APM) is produced, the anhydride produced here is then contacted with L-phenylalanine or its methyl ester (hereinafter referred to as PM). Let
N-formyl-α-L-aspartyl-L-phenylalanine (hereinafter referred to as F-α-AP) or its methyl ester (hereinafter referred to as F-α-APM) is obtained (hereinafter, this reaction is referred to as a condensation reaction). However, if formic acid remains in the condensation reaction, the reaction itself is inhibited and N-formyl-α-L-aspartyl-L-phenylalanine or its methyl ester (α-form), N-formyl-β-. L-Aspartyl-L-phenylalanine or the function of lowering the production ratio of methyl ester (β-form) thereof. There is currently no effective means to convert the β-form once generated to the α-form in the subsequent deformylation step, and the β-APM derived from the β-form is not present.
Has no sweetness, so α-form and β-form in the condensation reaction step
A decrease in the production ratio (α / β ratio) of the body means an increase in loss, that is, an increase in the raw materials and the basic unit of utility.

As a method for removing this formic acid, there is also a method (USP3933781) of evaporating the anhydrous reaction solution to dryness, but once considering the stability of the reaction product and the operability on an industrial scale, It is desirable to adopt a method in which the anhydride suspended in the liquid is subjected to solid-liquid separation, and the separated anhydride crystals are used for the condensation reaction. At this time, it is also known that the separation yield can be increased by carrying out this separation in the presence of an aromatic hydrocarbon and / or a halogenated hydrocarbon (JP-A-51-91210).

From the standpoint of minimizing the amount of residual solvent in the anhydrous crystals after separation, it is desirable to separate the anhydride and the reaction solution by centrifugation. At this time, however, there are problems peculiar to this system. Will occur. That is, first of all,
The anhydrous crystal produced by the above method is a columnar crystal having a diameter and a height of about 1 mm to 3 mm, and the crystal size is very large, the true specific gravity is large, and the sedimentation property is very good. Therefore, if the suspension is supplied after the basket with the filter cloth is rotated, the filtration is instantaneously terminated, and as a result, the separated crystals of the anhydrous crystals deposited with a certain thickness in the basket, that is, The degree of cake deposition is localized, resulting in non-uniform cake thickness. This impairs driving safety and makes continuous operation difficult. As a method to prevent such an imbalance of the cake, it is possible to rotate the basket at an extremely low speed to supply the suspension, but since the cake concentrates on the lower part of the basket at a too low speed, the cake is accumulated. There is a limit to the reduction of the rotation speed, and if the rotation speed exceeds the limit, the imbalance cannot be completely prevented.

[0006] Once the cake is imbalanced during the liquid supply, the subsequent filtration and liquid removal must be performed at an extremely low rotational speed for safety.
The cake finally obtained has a high liquid content, that is, a large amount of residual formic acid.

Further, when cake cleaning is performed using a cleaning liquid, this leads to a problem that the cleaning efficiency of the cake varies depending on the local area where the cake thickness is different. It has been experienced that the cleaning efficiency becomes extremely poor compared to. Considering the influence of the residual formic acid on the condensation reaction yield described above, it is clear that these problems become extremely serious in the case of producing α-APM as a final product.

Further, comparing the affinity between the anhydride and each solvent component (formic acid, acetic acid, acetic anhydride, aromatic hydrocarbon, etc.) in the anhydrous reaction solution, the affinity with formic acid is particularly large, and thus the reaction solution The formic acid concentration in the boundary layer around the anhydrous crystals suspended therein is higher than that in other parts of the reaction solution. Therefore, from the viewpoint of reducing the residual formic acid, it is desirable to first stir vigorously when centrifuging to make the boundary layer as thin as possible and then to perform filtration, but as long as a normal centrifugation method is used, Filtration will proceed rapidly without a room for thinning the boundary layer after a gradual flow state in which the suspension is pumped or headed.

Due to the above-mentioned various problems, it is impossible to use the centrifugal separation method for the separation of the anhydrides, and it has been usual to carry out the separation using a pressure type flat plate filter until now. Has become. However, this is cumbersome and is not suitable for large-scale production, so when the production scale is large, the separation of the anhydride is not necessary at the sacrifice of the yield, that is, a stoichiometric amount of formic acid relative to aspartic acid. The actual situation is that the dehydration reaction using must be carried out.

[0010]

The problem to be solved by the invention is to prevent imbalance of the anhydrous cake during the production of the anhydrous product and the separation of the suspension thereof, thereby improving the operational safety and the deliquability of the cake. In addition, the centrifugation conditions were established so that the cake was evenly adhered to enhance the washing efficiency in cake washing and the boundary layer around the anhydrous crystals immediately before filtration was thinned, and thus anhydrous crystals with a low residual formic acid content were established. Is to be able to obtain. In addition, α // is obtained by reacting the anhydrous crystal with L-phenylalanine or PM.
High β ratio, that is, high yield of F-α-AP or F-α
-To establish a process for manufacturing APM.

[0011]

Means for Solving the Problems The inventors of the present invention have earnestly studied to solve the above problems, and as a result, have obtained the following new findings.

That is, when centrifuging an anhydrous suspension, the first half of the total amount of suspension supplied at one time, which has a particularly low filtration resistance and a high filtration rate, is supplied at a spin rate of 100 [mmHg] or more. If it is done under pressure, the imbalance of the cake can be prevented, and the deliquoring rate of the cake is greatly improved, and the thickness of the cake after all the remaining suspension is supplied becomes uniform. It was found that the cleaning efficiency during cake cleaning was dramatically increased. Here, applying back pressure means making the pressure on the filtrate side higher than that on the supply suspension side during filtration, and the back pressure value means the difference between the pressure values on both sides.

Further, according to this method, the suspension time becomes longer in the extremely vigorous stirring state due to the shearing force of the rotating basket, so that the liquid phase adsorption of formic acid on the crystal surface is promoted. It was found that it is possible to carry out filtration while avoiding it.

By carrying out centrifugation under such conditions, it becomes possible to obtain an anhydrous crystal having a small residual formic acid content, and by reacting the crystal with L-phenylalanine or PM, the β-form secondary compound is reacted. It was also clarified that F-α-AP or F-α-APM can be obtained in a high yield while suppressing the raw material.

The present inventors applied these new findings to an actual process for producing an anhydride, thereby enabling the anhydrate to be dehydrated under excess formic acid on the premise of centrifugation of the anhydride.
The present invention has been completed by increasing the dehydration yield and significantly reducing the loss derived from the by-product β-body in the subsequent step.

That is, the present invention is a method for producing N-formyl-L-aspartic acid anhydride by reacting L-aspartic acid with formic acid in an amount of 1.05 times or more the molar amount of acetic anhydride and aspartic acid. When centrifuging the N-formyl-L-aspartic acid anhydride suspension in (1), the supply of the suspension to the separation device is started with a back pressure of 100 [mmHg] or more applied. (2) At least when half or more of the suspension has been supplied, back pressure is not applied, and (3) filtration and / or cake deliquoring are performed and cake is washed as necessary. Is a method for producing N-formyl-L-aspartic acid anhydride. Further, the N-formyl-L-aspartic acid anhydride crystal thus obtained is dissolved or suspended in acetic acid to obtain L-phenylalanine or L-
N-formyl-α-L-aspartyl-L-phenylalanine or N-formyl-α-L-aspartyl-L-phenylalanine methyl ester is synthesized by reacting with phenylalanine methyl ester. -L-Aspartyl-L
-Phenylalanine or N-formyl-α-L-aspartyl-L-phenylalanine methyl ester.

The separation of the anhydrides here is premised on the use of an excess of formic acid with respect to aspartic acid in the dehydration reaction. Considering the yield of the dehydration reaction, the amount thereof is preferably 1.05 times or more the molar amount of aspartic acid. Further, a catalyst may be added to increase the yield of the dehydration reaction. As the catalyst in this case, the substances disclosed in JP-B-4-986 such as magnesium acetate can be used.

If the above-mentioned effect on the separation of the anhydride is to be expected, the value of the back pressure applied in the present invention depends on the value of the centrifugal force in the state without back pressure, but is at least 100 [mmHg].
It is necessary to be above, preferably 350 [mmHg] or more, more preferably 760 [mmHg] or more. The higher the back pressure is, the greater the effect of preventing the imbalance is, but if it is too high, the processing capacity of the apparatus itself is lowered due to the decrease in the filtration rate. In addition, the back pressure must be applied while at least half or more of the total suspension supplied in one separation is supplied, and it is preferable to supply the entire amount with the back pressure applied. Good. Although it is effective to continue applying back pressure for a certain period of time after the total amount is supplied, the time required for one separation will increase accordingly, so it is necessary to decide the optimum time after considering the margin regarding the processing capacity of the separator. is there.

The back pressure is applied as follows: (1) A throttle valve is provided in the outlet pipe of the filtrate, (2) the basket is doubled, and a filter cloth is put between the inner part and the outer part, There is a method in which the filtrate is allowed to flow to a portion and then the water level when the filtrate comes out of the basket is provided inside the filter cloth surface. In the case of (1), if a vertical centrifuge is used, the filtrate is allowed to collect between the rotating basket and the casing on the outside thereof, which corresponds to the liquid surface of the filtrate layer and the liquid column of the throttle valve. Apply back pressure.
In the case of (2), a basket having the structure shown in FIG. 1 is used. a is a filter cloth, and b is a tube for skimming the filtrate. During the separation, a back pressure corresponding to the height difference h between the filter cloth surface a and the water level c of the filtrate is applied. The structure of a separator having a basket having such a structure is Japanese Patent Publication No. 53-
The value of the back pressure can be adjusted by the number of rotations of the basket and the depth of insertion of the skimming tube, as disclosed in 21532 and widely sold and known, if this device is used in the present invention.

The anhydrous product may be separated by separating the anhydrous reaction liquid as it is, or may be added after adding a solvent capable of reducing the solubility of the anhydrous product. As this solvent, aromatic hydrocarbons such as toluene and xylene disclosed in JP-A-51-91210 can be used.

When the thus obtained anhydrous crystal is reacted with L-phenylalanine or L-phenylalanine methyl ester (PM), it is preferable to use acetic acid as a reaction solvent. Specifically, anhydrous crystals can be dissolved or suspended in acetic acid, and L-phenylalanine can be added as a solid solution, and PM can be added and reacted as a solution dissolved in a solvent such as toluene.

[0022]

EFFECTS OF THE INVENTION According to the method of the present invention, as an industrial scale operation, it is possible to dehydrate an excess formic acid on the premise of centrifuging the anhydride, thereby improving the dehydration yield and the residual formic acid content. By using an anhydrous crystal with a low content in the condensation step, the loss derived from the by-product β-form in the subsequent step is significantly reduced, and thus it is a method of high practical value.

[0023]

EXAMPLES The present invention will be described in more detail below with reference to examples.

(Examples 1 and 2) Peeler centrifuge Hz100Si (basket diameter 1000 mm, manufactured by Mitsubishi Kakoki Co., Ltd., which is a centrifugal separator having the basket structure shown in FIG.
The separation experiment of the dehydration reaction liquid was carried out using a filtration area of 1.57 m2). As the dehydration reaction liquid, magnesium acetate and L-aspartic acid are added to a mixed solution of formic acid and acetic anhydride to cause the dehydration reaction, and then toluene is added to adjust the temperature.
A suspension cooled to 5 ° C was used. The molar ratio of input formic acid to input aspartic acid during the reaction was set to 1.5.
The concentrations of N-formyl-L-aspartic anhydride, formic acid, acetic acid, and toluene in the reaction suspension were 16.0 and
It was 3.1, 26.8 and 49.9 wt%.

The total amount of suspension supplied in one separation experiment was kept constant at 300 L, and the liquid was supplied at 50 L at intervals of 5 seconds.
Each was divided into four times. At the time of starting the liquid supply, a back pressure adjusted to a certain value is applied according to the number of rotations of the basket and the depth of inserting the skimming tube, and the number of rotations of the basket is appropriately adjusted after the 0th to 4th liquid supply among the four times of liquid supply The highest (14
(00 rpm) and the skimming tube was inserted all the way to release the back pressure and perform the remaining separation.

After completion of the separation, the cake was washed with 100 L of toluene, and the removal rate of formic acid was calculated based on the formula shown in Formula 1.

[0027]

[Equation 1]

Table 1 shows the results of the operating conditions and the formic acid removal rate in each separation experiment.

[0029]

[Table 1]

(Examples 3 to 4) Magnesium acetate was added to a mixed solution of formic acid and acetic anhydride, and then L-aspartic acid was added so that the molar ratio of formic acid and aspartic acid was 1.3: 1, followed by dehydration. The reaction was allowed to take place. The concentrations of N-formyl-L-aspartic anhydride, formic acid, and acetic acid in the reaction suspension after the reaction were 32.7, 4.2, and 54.8 wt%, respectively. 150 L of this reaction suspension was separated by the following two separation methods, and washed with cake using 100 L of acetic acid to obtain wet crystals of N-formyl-L-aspartic acid anhydride. (1) Separator: Peeler centrifuge Hz100Si manufactured by Mitsubishi Kakoki Co., Ltd. (basket diameter 1000 m, same as in Example 1)
m, filtration area 1.57m2) Condition: Adjusting the depth of inserting the skimming tube, the suspension is supplied with a back pressure of 800mmHg by 80L, which is about half of the total, and then the back pressure is released. Then, the remaining liquid supply, cake washing, and liquid removal were performed. (2) Separator: Vertical discharge vertical centrifuge (basket diameter 10
70mm, filtration area 1.38m2) Condition: In order to prevent the imbalance of the cake, 30 L of the suspension was started to be supplied at low speed, but the number of rotations of the basket was increased because the filtration was concentrated at the bottom of the basket. Was manually adjusted between low and high speeds to provide the remaining liquid supply. Even so, it is not possible to prevent the cake from being unbalanced, and the deliquoring of the cake after washing is 1 / max.
It could only be done at 4 rpm.

When the formic acid content in the wet crystals obtained in (1) and (2) was measured, the results shown in Table 2 were obtained.

These wet crystals are then suspended in acetic acid,
The mixture was heated to 45 ° C., and an equimolar amount of L-phenylalanine was added to the N-formyl-L-aspartic anhydride in the suspension to carry out a condensation reaction. The content of N-formyl-α-L-aspartyl-L-phenylalanine and N-formyl-β-L-aspartyl-L-phenylalanine in the reaction solution after the reaction was measured by HPLC, and their production ratio (α / β ratio) was determined. Table 2 shows the results.

Further, these wet crystals were suspended in acetic acid and kept at 25 ° C. so that the toluene solution of L-phenylalanine methyl ester had a molar ratio of N-formyl-L-aspartic anhydride to 0.97. A condensation reaction was carried out by adding. N-formyl-α-in the reaction solution after the reaction
The contents of L-aspartyl-L-phenylalanine methyl ester and N-formyl-β-L-aspartyl-L-phenylalanine methyl ester were measured by HPLC to determine their production ratio (α / β ratio). Table 2 shows the results
Shown in.

[0034]

[Table 2]

[Brief description of drawings]

FIG. 1 is a sectional view showing an outline of a centrifuge having a basket structure.

Claims (8)

[Claims] 1. A method for producing N-formyl-L-aspartic acid anhydride by reacting L-aspartic acid with acetic anhydride and a formic acid in an amount 1.05 times or more the molar amount of aspartic acid. When centrifuging the N-formyl-L-aspartic acid anhydride suspension after the reaction in the presence or absence of the reaction (1), a back pressure of 100 [mmHg] or more is applied to the suspension. Starting the supply to the separation device, (2) at least when half or more of the suspension has been completed, a back pressure is not applied, and (3) filtration and / or cake deliquoring are continuously required. A process for producing N-formyl-L-aspartic anhydride, which comprises washing the cake according to 2. The N-formyl-L-aspartic acid anhydride crystal obtained in claim 1 is dissolved or suspended in acetic acid and reacted with L-phenylalanine to produce N-
Formyl-α-L-aspartyl-L-phenylalanine is synthesized, and N-formyl-α-L-
A method for producing aspartyl-L-phenylalanine. 3. The N-formyl-L-aspartic acid anhydride crystal obtained in claim 1 is dissolved or suspended in acetic acid and reacted with L-phenylalanine methyl ester to produce N-formyl-α-L. -Aspartyl-L-
A method for producing N-formyl-α-L-aspartyl-L-phenylalanine methyl ester, which comprises synthesizing phenylalanine methyl ester. 4. The method according to claim 1, 2 or 3, wherein the aromatic hydrocarbon used is a mixed solution of one or more of benzene, toluene or xylene. . 5. The method according to any one of claims 1 to 4, wherein the back pressure in (1) is 350 [mmHg] or more. 6. The method according to any one of claims 1 to 4, wherein the back pressure in (1) is 760 [mmHg] or more. 7. The method according to any one of claims 1 to 6, wherein the back pressure is released in (2) after the entire amount of the suspension is supplied. 8. A washing solution for washing the cake in (3), wherein a mixed solution of one or two of aromatic hydrocarbon and acetic acid added before separation is used. Item 8. The method according to any one of Items 7 to 7.